A group of several independent scientists at The University of Chicago seeks to create a coordinated program in sickle cell disease research. Their approaches vary widely, but they share a common interest: the erythrocyte in health and disease, sickle cell disease in particular. Their aims are to draw closer together around the topic of sickle cell disease; to create a highly interactive scientific group whose diverse interests will be synergistic; to foster new and better research, both individual and collaborative; and to expedite such research through coordinated sharing of scientific information, instrumentation, core facilities, patients, and data. The benefits of the program project will be the promotion of mutual education, new scientific insights, improved collaboration, and increased efficiency and economy of research through a central focus on sickle cell disease. This application seeks support for this program. The theme of this program is the biology of the erythrocyte in sickle cell disease. In that the research emanates from independent scientific programs, it is not unitary but diverse and complementary. The program thus draws strength from the breadth of its membership and a wide range of expertise. There is, nevertheless, considerable continuity in the scope of the research. Huttenlocher seeks to relieve the occlusive cerebral vascular disease arising from the compromised rheology of sickled cells. Shen proposes to elucidate the structural basis for the irreversibly-sickled cell; an altered sub-membrane filamentous network. Josephs will continue his characterization of hemoglobin S fibers by high resolution electron microscopy. Potel will apply computer techniques to the analysis of Josephs's EM data and Huttenlocher's positron emission tomographs. Steck will test a novel hypothesis which explains and promises to reverse the increased passive permeability of sickle cell membranes to small solutes. Goldwasser will study the expression of globin genes and Gross will study the control of their translation. Not all projects interact with all others; this would be an unrealistic goal for research programs that originate with investigators rather than with a single organizer. There is, however, a stong element of mutual interest that is bound to help advance the science in each subproject.